MET inhibition overcomes radiation resistance of glioblastoma stem‐like cells

Abstract

Glioblastoma (GBM) contains stem‐like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti‐apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC‐positive selection, induced by radiotherapy, into GSC eradication.

Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell Lung Cancer

“…MET is an important therapeutic target for multiple cancers (46–48) and increased expression has been associated with poor prognosis (48). Previous studies have implicated MET in therapeutic resistance to antiangiogenic therapies and radiation (46–48), and earlier reports suggested a role of MET in SCLC tumorigenesis and progression (49). We find that the combination of AZD1775 and a dual AXL/MET inhibitor, cabozantinib (FDA-approved for thyroid and renal cancers) overcomes acquired resistance to WEE1 inhibition even more than combinations with TP0903 or RAD001.…”

Magnetic hyperthermia therapy for the treatment of glioblastoma: a review of the therapy’s history, efficacy and application in humans

“…These cells are located beyond the contrast enhancing tumour visualised on magnetic resonance imaging (MRI) and are difficult to resect since they reside among healthy cells. The infiltrating cancer cells are known to be resistant to both chemotherapy and RT [8–10]. Recurrent tumours are especially resistant to therapies and difficult to treat [11].…”

Radiotherapy and Glioma Stem Cells: Searching for Chinks in Cellular Armor

“…GSCs expressing MET withstand radiation by activating ATM. Critically, xenograft mice treated with MET inhibitors and radiation did markedly better than control or monotherapy treated mice(10). In addition, another study on cancer stem cells from adenoid cystic carcinoma, which are also identified by expression of CD133, showed that expression of Notch and Sox, two GSC regulators, are key players in radioresistance.…”

“…A landmark study conducted by Rich and colleagues demonstrated that GSCs isolated from human tumor samples survive irradiation better than non-GSC matched populations(9, 10). This resistance in the face of radiation has been confirmed by many studies(11, 12).…”